1. Field of the Invention
The present disclosure relates generally to the fields of medicine, pharmaceutical agents, and chemotherapeutics. The present disclosure relates to texaphyrin conjugates and compositions, which can be used to treat cancer.
2. Description of Related Art
The use of platinum(IV) chemotherapeutic pro-drugs has several advantages over the use of platinum(II) chemotherapeutic agents including improved stability, diminished side effects, or increased kinetic inertness (Rosenberg, B. et al., Nature 205:698, 1965; Shi, Y. et al., Biochem. 107:6, 2012). While, these pro-drug formulations are potentially useful, in order to increase pharmaceutical activity, the compound must be activated by reduction to the cytotoxic platinum(II) complex to obtain high cytotoxicity. Activation is typically carried out by intracellular processes, photoreduction, or through the use of ligands activated under specific conditions (Elding, L. I. and Gustafson, L., Inorg. Chim. Acta 19:165, 1976; Davies, M. S. et al., Inorg. Chem. 47:7673, 2008; Drougge, L. and Elding, L. I., Inorg. Chim. Acta 121:175, 1986; Lemma, K. et al., Inorg. Chem. 39:1728, 2000; Huang, J. C. et al., Proc. Natl. Acad. Sci. USA 1:10394-10398, 1994; Chau, K. Y. et al., Exp. Cell Res. 241:269-272, 1998; He, Q. et al., Proc. Natl. Acad. Sci. USA, 97:5768-5772, 2000; Barnes, K. R. et al., J. Chem. Biol. 11:557, 2004). Unfortunately, these processes rely on other cellular processes or application of external stimuli, such as light, and typically must be optimized to obtain effective results. Furthermore, many of these activation methods lack specificity for cancer cells.
The limitations found in FDA approved platinum(II) agents, which are often unable to overcome pharmacologic and molecular mechanisms in resistant cancers, have provided an incentive to use texaphyrins to help localize platinum(II) drugs to cancer sites via formation of so-called texaphyrin conjugates as detailed in U.S. Pat. No. 6,207,660, incorporated herein by reference. However, the prior art agents described in U.S. Pat. No. 6,207,660 and subsequent reports (Arambula, et al. 2009; Arambula, J. F.; Siddik, Z.; et al. 2011; Arambula, J. F.; Preihs, C. et al. 2011; Arambula, et al. 2012), proved unsatisfactory, either because the compounds lacked appropriate stability features, did not display appropriate solubility profiles, or failed to overcome completely platinum resistance in platinum resistant cell lines. Moreover, these prior texaphyrin-based systems relied on the use of a conjugated Pt(II) center rather than a Pt(IV) species. Thus, these conjugates did not benefit from the advantages associated with the use of a Pt(IV) center, including improved stability, diminished side effects, or increased kinetic inertness, as enunciated above. Developing new texaphyrin-platinum(IV) therapeutic agents or compositions that overcome these recognized limitations, while still providing an appropriate activation mechanism, would be of pharmaceutical importance; it would provide inter alia improved treatments for cancers and be especially advantageous in treating those cancers that exhibit resistance to current Pt(II) and Pt(IV) chemotherapeutic agents.
As can be clearly seen, the development of new therapeutic agents and compositions containing a texaphyrin and a platinum(IV) complex are needed.